Characterization of Rheumatoid Arthritis Risk-Associated SNPs and Identification of Novel Therapeutic Sites Using an In-Silico Approach

SIMPLE SUMMARY: Rheumatoid arthritis (RA) is a complex disease resulting from multiple genetic and environmental pathogenic factors. The genetic factors include single-nucleotide polymorphisms (SNPs), which have been reported to be associated with RA, but their specific role in the pathogenesis of RA remains unexplained. This study explains the potential role of RA risk-associated SNPs in its pathogenesis in order to provide a basis for understanding the genetic complexity of RA. Several roles of these SNPs are described in this study, and may also aid in the design of a therapeutic strategy for RA. Furthermore, novel potential therapeutic sites have also been researched, resulting in the identification of three novel therapeutic targets. The therapeutic strategies for the treatment of RA include inflammatory pathway-targeting drugs, which alleviate inflammation in joints. There is always a need for novel therapeutic targets that can play a role in alleviating inflammation in autoimmune diseases including RA. Therefore, these novel therapeutic sites are very important, and further experimental studies are required. ABSTRACT: Single-nucleotide polymorphisms (SNPs) are reported to be associated with many diseases, including autoimmune diseases. In rheumatoid arthritis (RA), about 152 SNPs are reported to account for ~15% of its heritability. These SNPs may result in the alteration of gene expression and may also affect the stability of mRNA, resulting in diseased protein. Therefore, in order to predict the underlying mechanism of these SNPs and identify novel therapeutic sites for the treatment of RA, several bioinformatics tools were used. The damaging effect of 23 non-synonymous SNPs on proteins using different tools suggested four SNPs, including rs2476601 in PTPN22, rs5029941 and rs2230926 in TNFAIP3, and rs34536443 in TYK2, to be the most damaging. In total, 42 of 76 RA-associated intronic SNPs were predicted to create or abolish potential splice sites. Moreover, the analysis of 11 RA-associated UTR SNPs indicated that only one SNP, rs1128334, located in 3′UTR of ETS1, caused functional pattern changes in BRD-BOX. For the identification of novel therapeutics sites to treat RA, extensive gene–gene interaction network interactive pathways were established, with the identification of 13 potential target sites for the development of RA drugs, including three novel target genes. The anticipated effect of these findings on RA pathogenesis may be further validated in both in vivo and in vitro studies.